Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRASG12D-mutated non-small-cell lung cancer

B. Ricciuti; J. V. Alessi; A. Elkrief; X. Wang; A. Cortellini; Y. Y. Li; V. R. Vaz; H. Gupta; F. Pecci; A. Barrichello; G. Lamberti; T. Nguyen; J. Lindsay; B. Sharma; K. Felt; S. J. Rodig; M. Nishino; L. M. Sholl; D. A. Barbie; M. V. Negrao; J. Zhang; A. D. Cherniack; J. V. Heymach; M. Meyerson; C. Ambrogio; P. A. Jänne; K. C. Arbour; D. J. Pinato; F. Skoulidis; A. J. Schoenfeld; M. M. Awad; J. Luo

doi:10.1016/j.annonc.2022.07.005

Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRAS^G12D-mutated non-small-cell lung cancer

B. Ricciuti, J. V. Alessi, A. Elkrief, X. Wang, A. Cortellini, Y. Y. Li, V. R. Vaz, H. Gupta, F. Pecci, A. Barrichello, G. Lamberti, T. Nguyen, J. Lindsay, B. Sharma, K. Felt, S. J. Rodig, M. Nishino, L. M. Sholl, D. A. Barbie, M. V. NegraoJ. Zhang, A. D. Cherniack, J. V. Heymach, M. Meyerson, C. Ambrogio, P. A. Jänne, K. C. Arbour, D. J. Pinato, F. Skoulidis, A. J. Schoenfeld, M. M. Awad, J. Luo

Thoracic Head & Neck Medical Oncology

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

Abstract

Background: Allele-specific KRAS inhibitors are an emerging class of cancer therapies. KRAS-mutant (KRAS^MUT) non-small-cell lung cancers (NSCLCs) exhibit heterogeneous outcomes, driven by differences in underlying biology shaped by co-mutations. In contrast to KRAS^G12C NSCLC, KRAS^G12D NSCLC is associated with low/never-smoking status and is largely uncharacterized. Patients and methods: Clinicopathologic and genomic information were collected from patients with NSCLCs harboring a KRAS mutation at the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, and Imperial College of London. Multiplexed immunofluorescence for CK7, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), Foxp3, and CD8 was carried out on a subset of samples with available tissue at the DFCI. Clinical outcomes to PD-(L)1 inhibition ± chemotherapy were analyzed according to KRAS mutation subtype. Results: Of 2327 patients with KRAS-mutated (KRAS^MUT) NSCLC, 15% (n = 354) harbored KRAS^G12D. Compared to KRAS^non-G12D NSCLC, KRAS^G12D NSCLC had a lower pack-year (py) smoking history (median 22.5 py versus 30.0 py, P < 0.0001) and was enriched in never smokers (22% versus 5%, P < 0.0001). KRAS^G12D had lower PD-L1 tumor proportion score (TPS) (median 1% versus 5%, P < 0.01) and lower tumor mutation burden (TMB) compared to KRAS^non-G12D (median 8.4 versus 9.9 mt/Mb, P < 0.0001). Of the samples which underwent multiplexed immunofluorescence, KRAS^G12D had lower intratumoral and total CD8⁺PD1⁺ T cells (P < 0.05). Among 850 patients with advanced KRAS^MUT NSCLC who received PD-(L)1-based therapies, KRAS^G12D was associated with a worse objective response rate (ORR) (15.8% versus 28.4%, P = 0.03), progression-free survival (PFS) [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.45-2.00, P = 0.003], and overall survival (OS; HR 1.45, 1.05-1.99, P = 0.02) to PD-(L)1 inhibition alone but not to chemo-immunotherapy combinations [ORR 30.6% versus 35.7%, P = 0.51; PFS HR 1.28 (95%CI 0.92-1.77), P = 0.13; OS HR 1.36 (95%CI 0.95-1.96), P = 0.09] compared to KRAS^non-G12D. Conclusions: KRAS^G12D lung cancers harbor distinct clinical, genomic, and immunologic features compared to other KRAS-mutated lung cancers and worse outcomes to PD-(L)1 blockade. Drug development for KRAS^G12D lung cancers will have to take these differences into account.

Original language	English (US)
Pages (from-to)	1029-1040
Number of pages	12
Journal	Annals of Oncology
Volume	33
Issue number	10
DOIs	https://doi.org/10.1016/j.annonc.2022.07.005
State	Published - Oct 2022

Keywords

G12D
KRAS
NSCLC
PD-(L)1 blockade

ASJC Scopus subject areas

Hematology
Oncology

Access to Document

10.1016/j.annonc.2022.07.005

Cite this

Ricciuti, B., Alessi, J. V., Elkrief, A., Wang, X., Cortellini, A., Li, Y. Y., Vaz, V. R., Gupta, H., Pecci, F., Barrichello, A., Lamberti, G., Nguyen, T., Lindsay, J., Sharma, B., Felt, K., Rodig, S. J., Nishino, M., Sholl, L. M., Barbie, D. A., ... Luo, J. (2022). Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRAS^G12D-mutated non-small-cell lung cancer. Annals of Oncology, 33(10), 1029-1040. https://doi.org/10.1016/j.annonc.2022.07.005

Ricciuti, B, Alessi, JV, Elkrief, A, Wang, X, Cortellini, A, Li, YY, Vaz, VR, Gupta, H, Pecci, F, Barrichello, A, Lamberti, G, Nguyen, T, Lindsay, J, Sharma, B, Felt, K, Rodig, SJ, Nishino, M, Sholl, LM, Barbie, DA, Negrao, MV , Zhang, J, Cherniack, AD, Heymach, JV, Meyerson, M, Ambrogio, C, Jänne, PA, Arbour, KC, Pinato, DJ, Skoulidis, F, Schoenfeld, AJ, Awad, MM & Luo, J 2022, 'Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRAS^G12D-mutated non-small-cell lung cancer', Annals of Oncology, vol. 33, no. 10, pp. 1029-1040. https://doi.org/10.1016/j.annonc.2022.07.005

@article{59da41a5ed7f449297bddfd4f9b2c930,

title = "Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRASG12D-mutated non-small-cell lung cancer",

abstract = "Background: Allele-specific KRAS inhibitors are an emerging class of cancer therapies. KRAS-mutant (KRASMUT) non-small-cell lung cancers (NSCLCs) exhibit heterogeneous outcomes, driven by differences in underlying biology shaped by co-mutations. In contrast to KRASG12C NSCLC, KRASG12D NSCLC is associated with low/never-smoking status and is largely uncharacterized. Patients and methods: Clinicopathologic and genomic information were collected from patients with NSCLCs harboring a KRAS mutation at the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, and Imperial College of London. Multiplexed immunofluorescence for CK7, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), Foxp3, and CD8 was carried out on a subset of samples with available tissue at the DFCI. Clinical outcomes to PD-(L)1 inhibition ± chemotherapy were analyzed according to KRAS mutation subtype. Results: Of 2327 patients with KRAS-mutated (KRASMUT) NSCLC, 15% (n = 354) harbored KRASG12D. Compared to KRASnon-G12D NSCLC, KRASG12D NSCLC had a lower pack-year (py) smoking history (median 22.5 py versus 30.0 py, P < 0.0001) and was enriched in never smokers (22% versus 5%, P < 0.0001). KRASG12D had lower PD-L1 tumor proportion score (TPS) (median 1% versus 5%, P < 0.01) and lower tumor mutation burden (TMB) compared to KRASnon-G12D (median 8.4 versus 9.9 mt/Mb, P < 0.0001). Of the samples which underwent multiplexed immunofluorescence, KRASG12D had lower intratumoral and total CD8+PD1+ T cells (P < 0.05). Among 850 patients with advanced KRASMUT NSCLC who received PD-(L)1-based therapies, KRASG12D was associated with a worse objective response rate (ORR) (15.8% versus 28.4%, P = 0.03), progression-free survival (PFS) [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.45-2.00, P = 0.003], and overall survival (OS; HR 1.45, 1.05-1.99, P = 0.02) to PD-(L)1 inhibition alone but not to chemo-immunotherapy combinations [ORR 30.6% versus 35.7%, P = 0.51; PFS HR 1.28 (95%CI 0.92-1.77), P = 0.13; OS HR 1.36 (95%CI 0.95-1.96), P = 0.09] compared to KRASnon-G12D. Conclusions: KRASG12D lung cancers harbor distinct clinical, genomic, and immunologic features compared to other KRAS-mutated lung cancers and worse outcomes to PD-(L)1 blockade. Drug development for KRASG12D lung cancers will have to take these differences into account.",

keywords = "G12D, KRAS, NSCLC, PD-(L)1 blockade",

author = "B. Ricciuti and Alessi, {J. V.} and A. Elkrief and X. Wang and A. Cortellini and Li, {Y. Y.} and Vaz, {V. R.} and H. Gupta and F. Pecci and A. Barrichello and G. Lamberti and T. Nguyen and J. Lindsay and B. Sharma and K. Felt and Rodig, {S. J.} and M. Nishino and Sholl, {L. M.} and Barbie, {D. A.} and Negrao, {M. V.} and J. Zhang and Cherniack, {A. D.} and Heymach, {J. V.} and M. Meyerson and C. Ambrogio and J{\"a}nne, {P. A.} and Arbour, {K. C.} and Pinato, {D. J.} and F. Skoulidis and Schoenfeld, {A. J.} and Awad, {M. M.} and J. Luo",

note = "Publisher Copyright: {\textcopyright} 2022 European Society for Medical Oncology",

year = "2022",

month = oct,

doi = "10.1016/j.annonc.2022.07.005",

language = "English (US)",

volume = "33",

pages = "1029--1040",

journal = "Annals of Oncology",

issn = "0923-7534",

publisher = "Oxford University Press",

number = "10",

}

TY - JOUR

T1 - Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRASG12D-mutated non-small-cell lung cancer

AU - Ricciuti, B.

AU - Alessi, J. V.

AU - Elkrief, A.

AU - Wang, X.

AU - Cortellini, A.

AU - Li, Y. Y.

AU - Vaz, V. R.

AU - Gupta, H.

AU - Pecci, F.

AU - Barrichello, A.

AU - Lamberti, G.

AU - Nguyen, T.

AU - Lindsay, J.

AU - Sharma, B.

AU - Felt, K.

AU - Rodig, S. J.

AU - Nishino, M.

AU - Sholl, L. M.

AU - Barbie, D. A.

AU - Negrao, M. V.

AU - Zhang, J.

AU - Cherniack, A. D.

AU - Heymach, J. V.

AU - Meyerson, M.

AU - Ambrogio, C.

AU - Jänne, P. A.

AU - Arbour, K. C.

AU - Pinato, D. J.

AU - Skoulidis, F.

AU - Schoenfeld, A. J.

AU - Awad, M. M.

AU - Luo, J.

PY - 2022/10

Y1 - 2022/10

N2 - Background: Allele-specific KRAS inhibitors are an emerging class of cancer therapies. KRAS-mutant (KRASMUT) non-small-cell lung cancers (NSCLCs) exhibit heterogeneous outcomes, driven by differences in underlying biology shaped by co-mutations. In contrast to KRASG12C NSCLC, KRASG12D NSCLC is associated with low/never-smoking status and is largely uncharacterized. Patients and methods: Clinicopathologic and genomic information were collected from patients with NSCLCs harboring a KRAS mutation at the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, and Imperial College of London. Multiplexed immunofluorescence for CK7, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), Foxp3, and CD8 was carried out on a subset of samples with available tissue at the DFCI. Clinical outcomes to PD-(L)1 inhibition ± chemotherapy were analyzed according to KRAS mutation subtype. Results: Of 2327 patients with KRAS-mutated (KRASMUT) NSCLC, 15% (n = 354) harbored KRASG12D. Compared to KRASnon-G12D NSCLC, KRASG12D NSCLC had a lower pack-year (py) smoking history (median 22.5 py versus 30.0 py, P < 0.0001) and was enriched in never smokers (22% versus 5%, P < 0.0001). KRASG12D had lower PD-L1 tumor proportion score (TPS) (median 1% versus 5%, P < 0.01) and lower tumor mutation burden (TMB) compared to KRASnon-G12D (median 8.4 versus 9.9 mt/Mb, P < 0.0001). Of the samples which underwent multiplexed immunofluorescence, KRASG12D had lower intratumoral and total CD8+PD1+ T cells (P < 0.05). Among 850 patients with advanced KRASMUT NSCLC who received PD-(L)1-based therapies, KRASG12D was associated with a worse objective response rate (ORR) (15.8% versus 28.4%, P = 0.03), progression-free survival (PFS) [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.45-2.00, P = 0.003], and overall survival (OS; HR 1.45, 1.05-1.99, P = 0.02) to PD-(L)1 inhibition alone but not to chemo-immunotherapy combinations [ORR 30.6% versus 35.7%, P = 0.51; PFS HR 1.28 (95%CI 0.92-1.77), P = 0.13; OS HR 1.36 (95%CI 0.95-1.96), P = 0.09] compared to KRASnon-G12D. Conclusions: KRASG12D lung cancers harbor distinct clinical, genomic, and immunologic features compared to other KRAS-mutated lung cancers and worse outcomes to PD-(L)1 blockade. Drug development for KRASG12D lung cancers will have to take these differences into account.

AB - Background: Allele-specific KRAS inhibitors are an emerging class of cancer therapies. KRAS-mutant (KRASMUT) non-small-cell lung cancers (NSCLCs) exhibit heterogeneous outcomes, driven by differences in underlying biology shaped by co-mutations. In contrast to KRASG12C NSCLC, KRASG12D NSCLC is associated with low/never-smoking status and is largely uncharacterized. Patients and methods: Clinicopathologic and genomic information were collected from patients with NSCLCs harboring a KRAS mutation at the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, and Imperial College of London. Multiplexed immunofluorescence for CK7, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), Foxp3, and CD8 was carried out on a subset of samples with available tissue at the DFCI. Clinical outcomes to PD-(L)1 inhibition ± chemotherapy were analyzed according to KRAS mutation subtype. Results: Of 2327 patients with KRAS-mutated (KRASMUT) NSCLC, 15% (n = 354) harbored KRASG12D. Compared to KRASnon-G12D NSCLC, KRASG12D NSCLC had a lower pack-year (py) smoking history (median 22.5 py versus 30.0 py, P < 0.0001) and was enriched in never smokers (22% versus 5%, P < 0.0001). KRASG12D had lower PD-L1 tumor proportion score (TPS) (median 1% versus 5%, P < 0.01) and lower tumor mutation burden (TMB) compared to KRASnon-G12D (median 8.4 versus 9.9 mt/Mb, P < 0.0001). Of the samples which underwent multiplexed immunofluorescence, KRASG12D had lower intratumoral and total CD8+PD1+ T cells (P < 0.05). Among 850 patients with advanced KRASMUT NSCLC who received PD-(L)1-based therapies, KRASG12D was associated with a worse objective response rate (ORR) (15.8% versus 28.4%, P = 0.03), progression-free survival (PFS) [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.45-2.00, P = 0.003], and overall survival (OS; HR 1.45, 1.05-1.99, P = 0.02) to PD-(L)1 inhibition alone but not to chemo-immunotherapy combinations [ORR 30.6% versus 35.7%, P = 0.51; PFS HR 1.28 (95%CI 0.92-1.77), P = 0.13; OS HR 1.36 (95%CI 0.95-1.96), P = 0.09] compared to KRASnon-G12D. Conclusions: KRASG12D lung cancers harbor distinct clinical, genomic, and immunologic features compared to other KRAS-mutated lung cancers and worse outcomes to PD-(L)1 blockade. Drug development for KRASG12D lung cancers will have to take these differences into account.

KW - G12D

KW - KRAS

KW - NSCLC

KW - PD-(L)1 blockade

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